Preparation of hydroquinone amide compounds with antioxidant properties

This application is a 371 of PCT/FR2009/000233, filed Mar. 6, 2009.

The present invention concerns the preparation of hydroquinone-amide compounds that have antioxidant properties derived from an arylacetic acid comprising at least two hydroxy and amine or amino-alcohol groups that correspond to formula (I)

with R=alkyl (—C n H 2n+1 )

or R=hydroxyalkyl (—C n H n2+1 O)

or R=dihydroxyalkyl (—C n H n2+1 O 2 )

n being a number between 1 and 30.

Compounds (I) have the aromatic structure of reduced or ubiquinol coenzymes Q of formula (II)

which are themselves a reduced form of coenzymes Q or ubiquinones of formula (III), known for their antioxidant and free radical inhibiting properties in humans ([in English:] B. Halliwell and J. Gutteridge—Free Radicals in Biology and Medicine—1998).

Ubiquinones or coenzymes Q n , where n is the number of isoprene units in the R 1 chain, are lipophilic molecules made up of benzoquinone and a hydrophobic trans-polyisoprene chain that ensures stability in an organic medium.

In humans especially, the coenzyme Q 10 of formula (III) with n=10, after in vivo reduction in hydroquinone of formula (II) per the reversible reaction (1), is involved in mitochondria during cellular respiration, in the production of adenosine triphosphate (ATP), and in slowing cellular aging by capturing free radicals per reaction (2).

([In English:] S. Yamashita—Detection of ubiquinol and ubiquinone as a marker of oxidative stress, Anal. Biochemistry, 1997, 250 p. 66).

The compounds (III) are obtained industrially through costly fermentation or multiple-step synthesis, which limits their use on a large scale as an antioxidant for the prevention of degenerative diseases and human aging—the appearance of skin (wrinkles), cardiovascular diseases, neurodegenerative diseases and cancers—by efficiently capturing the free radicals that degrade cellular membranes and lipoproteins.

The object of the invention is to obtain antioxidant compounds that have the above properties, are stable and non-toxic, miscible in both lipid and aqueous media, which can effectively penetrate into cutaneous tissues.

These compounds (I) have the aromatic nucleus of ubiquinols (II) and lend themselves to the oxidation-reduction reaction (1).

They are obtained through the amidation of dihydroxy-2,5 dimethoxy-3,4 methyl-5 benzene acetic acid (V) in the form of its cyclic derivative (VI), by condensation with an amine of formula RNH 2 where R represents:

either a linear or branched R′ alkyl chain comprising 1 to 30 carbon atoms: formula (Ia),

or a hydroxy alkyl chain:

in which R″ is a hydrogen atom or a linear or branched chain of 1 to 28 carbon atoms.

For the uses cited above, amino-2-dodecanol-1 is preferred, with

R″=decyl (n-C 10 H 21 ): formula (Ib).

or a dihydroxy alkyl chain:

in which R′″ is a hydrogen atom or a linear or branched chain of 1 to 27 carbon atoms.

For the uses cited above, amino-2 propane diol-1,3 is preferred, with R′″═H: formula (Ic).

Amides (I) from amines R′NH 2 or amino-alcohols (VII) or (VIII) are formed through the simple heating in the absence of air of a molar equivalent of phenol lactone (VI) in a solvent medium:

reaction (3).

Lactone phenol (VI) has only been described once (V. G. Ramsey, Journal of the American Chemical Society, 1966, p. 1553).

It is obtained through the ozonolysis of coenzyme Q 9 (formula (III) with n=9), reduction with zinc, acetylation and then hydrolysis in an acid medium.

The high cost of the raw material along with the danger associated with the industrial use of ozone led us to develop a new method of synthesizing the compound (VI), in 3 stages, from coenzyme Q 0 (formula (III) with n=0),

an industrial raw material of coenzyme Q 10 , through reduction in hydroquinone of formula (II) in which R 1 ═H.

This reduction is conducted in sodium dithionite in an aqueous medium with quantitative yield.

Condensation with ethyl glyoxylate in the presence of a Lewis acid, especially titanium tetrachloride between −10° C. and 60° C. and particularly at 0° C., enables the new compound (IX) to be obtained with a quantitative yield (Synthesis 2004, p. 760).

The hydrogenation of (IX) in the presence of palladium on carbon in an acid medium like acetic acid in the presence of a strong acid and in particular in the presence of sulfuric acid between 0° C. and 120° C., preferably at 90° C., leads directly to lactone (VI) with an isolated yield of 68% from coenzyme Q 0 : reaction (4):

Lactone (VI), a solid, stable compound, is unexpectedly and advantageously directly condensed with the RNH 2 amines, without activation or protection of the free phenol function, leading directly to compounds (I).

The reaction of the amines or amino-alcohols with (VI) is performed through simple heating between 50° C. and 150° C. in an aprotic polar solvent like N-methylpyrrolidone, dimethylformamide or pyridine, in the absence of oxygen and preferably in the presence of a reducing agent such as an alkaline sulfite and preferably sodium dithionite.

After hydrolysis, the hydroquinone-amides (I) are isolated using appropriate techniques and purified through crystallization.

The compounds (I), stable as a solid, oxidize in the presence of oxygen in solution or in the presence of oxidizing agents, leading to quinone-amides (X).

The preferred oxidizing agent is iron chloride in an alcohol-water medium between 0° C. and 80° C., preferably in an ethanol-water medium at 20° C.

The antioxidant potential in solution of the compounds (I) is evaluated by measuring their reaction with the free radical diphenyl-picryl-hydrazide (XI) per C. T. Ho, S. Agric. Food Chem. 1999, p. 3975, using methyl gallate as a reference (XII).

The compounds (I) as a whole show antioxidant activity similar to that of the reference.

Applicant developed a process for preparing hydroquinone-amide compounds with antioxidant properties.

These compounds can be made into tablets, capsules, or as a mixture in cosmetic or pharmaceutical preparations using the usual techniques.

Of course, one skilled in the art can make various modifications to the devices or processes just described only as non-limiting examples, without leaving the framework of the invention.

The invention is illustrated by the following examples 1 to 5: